Patients over 15 years old requiring hospitalization for asthma are up to three times more likely to be female than male. Women comprised 64% of the asthma-associated deaths in 2009. Mainstay asthma therapies are often ineffective in women. Animal studies recapitulate the human disease: the hallmark features of allergic lung inflammation are worse in female mice compared to male mice and estrogen (E2) worsens lung inflammation. The lungs of both female mice and humans with asthma have greater numbers of alternatively activated (or M2) macrophages, correlating with worse lung function in humans. The broad objective of this proposal is to understand the molecular basis of sex differences in macrophages and their contribution to pathogenesis in allergic lung inflammation. The Specific Aims are to determine intrinsic sex differences in M2 differentiation in macrophages from male and females and the role of sex hormones (E2, DHT) and their receptors in regulating these differences in vitro and in vivo. Based on our preliminary data, we hypothesize that (i) macrophages from females express characteristic M2 phenotypic genes in response to IL-4 more highly compared to male cells and (ii) that E2 promotes and androgens suppress IL-4-induced M2 differentiation. We will test these hypotheses by defining differences in IL-4 receptor expression, IL-4-activated signal transduction pathways and induction of M2 gene expression in different mouse and human macrophage populations in vitro. We will also determine the effect of E2 and DHT on M2 differentiation, monocyte recruitment and macrophage turnover in the lung in vivo using mouse models of allergic lung inflammation in hormone-treated animals. Understanding these sex differences will help uncover novel targets for therapy in asthmatic women and tailor more effective, personalized therapies for asthma and allergic inflammation based on the sex of the patient.